1. Field of the invention
The present invention deals with the utilization of phenylisoquinoline derivatives and, namely, of 8-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydro-iso-quinoline hydrogen maleate (Nomifensine, Alival, Hoechst) and its derivatives in the differential diagnosis of disorders of hypotalamo-pituitary function.
2. Description of the prior art
The importance of some chemical agents as effective and suitable tools for the diagnosis of disease states is a well recognized event. In particular, the use of chemical agents in in vitro and/or in vivo test systems is of great aid for establishing whether certain symptoms may be attributed to a simple dysfunctional state or to an organic disturbance. In these instances, the use of appropriate diagnostic agents allows to clarify the etiology of the disturbance and hence to initiate the appropriate therapeutic trial.
In the last few years the studies of the central mechanisms involved in the regulation of anterior pituitary (AP) hormone secretion have led to the introduction of several functional tests in clinical practice. These tests are mainly based on:
(1) the use of neuroactive compounds, which are capable to affect the metabolism of neurotransmitters involved in the neuroendocrine control of AP function or,
(2) of hypothalamic regulatory hormones which exert their action directly at AP level.
From a theoretical ground, combined use of neuroactive drugs and hypothalamic hormones would be capable of unravelling the primary site(s) in the central nervous system (CNS) or/and the pituitary where the endocrine disturbance is located. This event, however, does not constantly occur, firstly, for the ability of the neuroendocrine drugs to affect also the AP gland, secondly, since the hyperplastic or tumoral pituitary may evidence receptors for the neuroactive drugs which are normally lacking in the intact AP gland, thirdly, as often the pathologic AP tissue is capable of responding normally to the hypophysiotropic stimuli.
Therefore, the diagnosis on the type and, hence, site(s) of the disturbance, quite often of paramount import for the prognosis and for a correct therapeutic approach cannot be made or, alternatively, is made only too late, when the alteration has already progressed too much.
The here-in-above mentioned difficulties, i.e. of developing (or possessing) effective diagnostic agents are even more apparent in the case of disturbances of the hypotalamo-pituitary system, on considering the multiple interactions existing between this neuroendocrine system and the rest of the body.
Thus, concomitant evaluation of AP hormone secretion in resting state or following administration of hypothalamic hormones (i.e. LH--RH) has been discouraging with regard to the differentiation between functional or pathologic states. A low basal plasma LH level concomitant to a blunted LH response to LH--RH in highly suggestive of a pituitary tumor in cases of hypogonadism, galactorrhea and hyperprolactinemia: however, even a normal LH and FSH response to LH--RH does not rule out the existence of a pituitary tumor. In hyperprolactinemic patients with pituitary microadenomas there is quite often an exaggerated FSH response to LH--RH; however, such an exaggerated FSH response reportedly is present also in some amenorrhea-galactorrhea patients with hyperprolactinemia but with no evidence of pituitary tumor.
The differential diagnosis between functional and pathologic states is further compounded by the fact that many cases originally classified as "functional" because of the finding of a radiologically normal pituitary fossa may be actually due to pituitary microadenomas.
From the foregoing it appears that until now, no functional test or series of tests have been introduced which allow a clear-cut differentation between "functional" or tumorous hyperprolactinemia, in spite of the fact that the usefulness of possessing neuroactive drugs capable of affecting central monoaminergic neurotransmission but unable to act directly at the level of receptor sites located on a normal or pathologic AP is cleraly emerging.